Protein kinases are important in cellular signal pathways that regulate various cell functions, including differentiation, proliferation, migration, and apoptosis. Deregulation of protein kinases is implicated in cancer and a number of other diseases.
Tyrosine kinases, a subclass of protein kinases, regulate target protein function through transfer of phosphate from ATP to the hydroxyl group of a target protein tyrosine. FMS-like tyrosine kinase 3 (“FLT3”), vascular endothelial growth factor receptor (“VEGFR”), and tyrosine-protein kinase Kit (“c-Kit”) are three tyrosine kinases that have been studied as attractive therapeutic targets in cancer treatment.
Mutations of FLT3, a receptor tyrosine kinase, can lead to development of cancer, e.g., acute myeloid leukemia. See Pratz et al., Current Drug Targets, 2010, 11(7), 781-9.
By binding to VEGFR and activating it via transphosphorylation, vascular endothelial growth factor, a signal protein, stimulates growth of new blood vessels. VEGFR has been identified as the predominant regulator of tumor angiogenesis. See Hicklin et al., J Clin Oncol., 2005, 23, 1011-1027.
c-Kit, also a receptor tyrosine kinase, is involved in intracellular signaling. The mutated form of c-Kit plays a crucial role in occurrence of some cancers. Inhibition of c-Kit has proved to be effective in treating gastrointestinal stromal tumor, acute myeloid leukemia, and melanoma. See Babaei et al., Drug Des Devel Ther., 2016 10, 2443-2459.
Aminothiazoles compounds, extensively explored as potent tyrosine kinase inhibitors, present several challenges as drug candidates. They possess poor kinase selectivity, often cause animal death in toxicity studies, and generally lack adequate in vivo exposure to exert desirable efficacy in pre-clinical or clinical studies.
There is a need to develop new aminothiazole compounds that specifically inhibit certain tyrosine kinases, demonstrate desirable safety profiles, and exert sufficient in vivo efficacy in treating target cancers.